SYNOPSIS: Examination of a large database led to the conclusion that treatment of community-acquired pneumonia in outpatients with narrower-spectrum agents (macrolides or doxycycline) was associated with similar clinical outcomes but with a lower incidence of adverse effects when compared to broader-spectrum therapy.
SOURCE: Butler AM, Nickel KB, Olsen MA, et al. Comparative safety of different antibiotic regimens for the treatment of outpatient community-acquired pneumonia among otherwise healthy adults. Clin Infect Dis. 2024;Oct 23:ciae519. doi: 10.1093/cid/ciae519. [Online ahead of print].
Butler and colleagues used the Merative MarketScan Commerical Database to examine adverse effects of narrow-spectrum vs. broad-spectrum antibiotic therapy of otherwise healthy adults (18-64 years of age) with community-acquired pneumonia (CAP) diagnosed in an outpatient setting. The database includes individuals with employer-sponsored commercial insurance as well as their spouses and dependents. For inclusion, subjects must have received a prescription for a guideline-recommended antibiotic on the day of diagnosis, but with the added inclusion of monotherapy with a β-lactam. Amoxicillin monotherapy was not included in the primary analysis since it had been added late to the guidelines. Macrolides and doxycycline were each considered to have narrow spectra, while broad-spectrum therapies were the respiratory fluoroquinolones, β-lactam monotherapy, β-lactam plus macrolide, and β-lactam plus doxycycline.
The final cohort included 145,137 individuals, of whom 63,474 (44%) received a macrolide, 56,388 (39%) received a fluoroquinolone, 11,301 (8%) received doxycycline, 9,652 (7%) were prescribed β-lactam monotherapy, and 4,322 (3%) received a β-lactam plus a macrolide. In addition, 612 patients were prescribed a β-lactam plus doxycycline, but these were excluded from analysis because of the small number. Approximately two-thirds (69%) of patients were seen in an office setting, while 16% were seen in an emergency department and 11% at urgent care sites.
A comparison of the narrow-spectrum agents (macrolides and doxycycline) demonstrated similar risks of adverse drug events (ADE), with the exception of a greater risk of nausea and/or vomiting in association with doxycycline (weighted risk difference [RD] per 100 treatment episodes, 0.22; 95% confidence interval [CI], 0.02, 0.45). However, each broad-spectrum regimen had a greater risk of ADEs when compared to macrolide monotherapy. Thus, nausea/vomiting/abdominal pain occurred more frequently with β-lactams (RD per 100, 0.32; 95% CI, 0.10-0.57), as did non-Clostridioides difficile diarrhea (RD per 100, 0.46; 95% CI, 0.25-0.68), and vulvovaginal candidiasis/vaginitis (RD per 100, 0.36; 95% CI, 0.09-0.69).
Commentary
The 2019 American Thoracic Society (ATS)/Infectious Diseases Society of America (IDSA) CAP guideline recommends that healthy adult outpatients be treated with either amoxicillin, doxycycline, or a macrolide (azithromycin or clarithromycin). The macrolide recommendation was conditional and restricted to areas where < 25% of Streptococcus pneumoniae were macrolide-resistant.1 A very recent review concurs with these recommendations.2 It is generally recommended that fluoroquinolone use be limited.
As acknowledged by the authors, this study has several limitations, many are the result of large database limitations. In general care, the diagnosis of pneumonia often may be incorrect and, furthermore, a large percentage of patients with pneumonia may not have a bacterial infection. There may be differences in tolerability of azithromycin and clarithromycin (it can be hoped that no one is using erythromycin), yet the two macrolides were lumped together in this analysis. As the authors indicated, they could not analyze ADEs relative to the duration of therapy. While non-C. difficile diarrhea is analyzed, there seems to be no mention of diarrhea due to C. difficile. Adults older than 64 years of age were excluded. Finally, those included in the database all were employed or had someone in the family who was employed, a factor that could be associated with general health.
Nonetheless, the results of this study demonstrated the greater tolerability of narrow-spectrum therapy and confirmed the importance of their preferential use in the management of otherwise healthy adult outpatients with CAP.
Stan Deresinski, MD, is Clinical Professor of Medicine, Stanford University.
References
- Metlay JP, Waterer GW, Long AC, et al. Diagnosis and treatment of adults with community-acquired pneumonia. An official clinical practice guideline of the American Thoracic Society and Infectious Diseases Society of America. Am J Respir Crit Care Med. 2019;200:e45-e67.
- Vaughn VM, Dickson RP, Horowitz JK, Flanders SA. Community-acquired pneumonia: A review. JAMA. 2024;332:1282-1295.
